Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

Acute care, secondary prevention, and outcomes after ischaemic and haemorrhagic stroke in men and women: a data-linkage study.

Introduction There is evidence that sex differences exist in stroke presentation, risk factors, severity, treatment, and outcomes. To further understand this, we explored how sex differences influence acute stroke management, secondary prevention prescribing and mortality outcomes in a well-characterised cohort of first-ever stroke patients in Scotland. Methods This is a retrospective, population-based, data-linkage study of stroke admissions to acute care hospitals in Scotland between 1 January 2011 and 31 December 2018. Data sources included the Scottish Stroke Care Audit (SSCA), the Prescribing Information System (PIS), the Scottish Morbidity Record 01 (SMR01), and the National Records of Scotland (NRS) Death Records. Multivariable logistic regression was used to explore the association between patient sex, acute stroke care and secondary prevention prescribing, while Cox proportional hazards models were used to explore the association between patient sex and all-cause mortality up to one year after index event. Results This study included 5901 patients with a first-ever intracerebral haemorrhage (ICH) and 47 087 patients with a first-ever acute ischaemic stroke (AIS). After an ICH, women had significantly lower odds of receiving all components of the stroke care bundle (adjusted odds ratio (aOR), 0.78; 95% confidence interval (CI), 0.69 - 0.87) and were less likely to be prescribed antihypertensives within ninety days after discharge (aOR, 0.78; 95% CI, 0.63 - 0.97) to usual place of residence. There was no sex difference in stroke care bundle achievement for those admitted with AIS, however, women had significantly lower odds of receiving antihypertensives, lipid-lowering drugs or oral anticoagulants (OAC) after discharge. The risk of all-cause mortality was lower in women at one year after both ICH (adjusted hazard ratio (aHR), 0.90; 95% CI, 0.83 - 0.98) and AIS (aHR, 0.91; 95% CI, 0.87 - 0.95) after adjusting for potential confounders. Conclusion The sex differences in stroke treatment and outcomes may be partly explained by the older age of women at the time of stroke, which influences stroke presentation, severity, and prognosis. However, following adjustment, women had reduced risk of all-cause mortality after both ICH and AIS.

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

Probing Momentum-Dependent Scattering in Uniaxially Stressed Sr_{2}RuO_{4} through the Hall Effect.

The largest Fermi surface sheet of the correlated metal Sr_{2}RuO_{4} can be driven through a Lifshitz transition between an electronlike and an open geometry by uniaxial stress applied along the [100] lattice direction. Here, we investigate the effect of this transition on the longitudinal resistivity ρ_{xx} and the Hall coefficient R_{H}. ρ_{xx}(T), when Sr_{2}RuO_{4} is tuned to this transition, is found to have a T^{2}logT form, as expected for a Fermi liquid tuned to a Lifshitz transition. R_{H} is found to become more negative as the Fermi surface transitions from an electronlike to an open geometry, opposite to general expectations from this change in topology. The magnitude of the change in R_{H} implies that scattering changes throughout the Brillouin zone, not just at the point in k space where the transition occurs. In a model of orbital-dependent scattering, the electron-electron scattering rate on sections of Fermi surface with xy orbital weight is found to decrease dramatically.

TEARS: a longitudinal investigation of the prevalence, psychological associations and trajectory of poststroke emotionalism.

OBJECTIVE: There are few longitudinal studies of poststroke emotionalism (PSE) and our understanding of the psychological associations of PSE is limited, constraining assessment of existing interventions and the development of new therapies. This study aimed to assess the prevalence and course of PSE over the first year poststroke, and its psychological associations. METHODS: Consenting stroke survivors who were physically and cognitively able to participate were assessed within 2 weeks, 6 and 12 months of stroke to determine PSE point prevalence using a diagnostic, semistructured PSE interview (Testing Emotionalism After Recent Stroke-Diagnostic Interview). At the same assessments, neuropsychological and disability status were determined using Hospital Anxiety and Depression Scale, Abbreviated Mental Test, National Institute of Health Stroke Scale, Barthel Index and Euro-Qol. RESULTS: Two hundred and seventy seven stroke survivors were recruited between 1 October 2015 and 30 September 2018. Diagnostic data were available at baseline for 228 of 277 cohort participants. Point prevalence for PSE was 27.2% at 2 weeks; estimated prevalence at 6 months adjusted for baseline was 19.9% and at 12 months 22.3%. PSE was associated with symptoms of anxiety and event-related distress. INTERPRETATION: PSE affects at least one in five stroke patients acutely following their stroke, and continues to affect one in eight longer term. PSE is associated with anxiety and event-related distress but is not simply a manifestation of mood disorder over time. Such psychological correlates may have implications for longer term social rehabilitation.

Post stroke intervention trial in fatigue (POSITIF): Randomised multicentre feasibility trial.

OBJECTIVE: To test the feasibility of a telephone delivered intervention, informed by cognitive behavioural principles, for post-stroke fatigue, and estimated its effect on fatigue and other outcomes. DESIGN: Randomised controlled parallel group trial. SETTING: Three Scottish stroke services. SUBJECTS: Stroke survivors with fatigue three months to two years post-stroke onset. INTERVENTIONS: Seven telephone calls (fortnightly then a 'booster session' at 16 weeks) of a manualised intervention, plus information about fatigue, versus information only. MAIN MEASURES: Feasibility of trial methods, and collected outcome measures (fatigue, mood, anxiety, social participation, quality of life, return to work) just before randomisation, at the end of treatment (four months after randomisation) and at six months after randomisation. RESULTS: Between October 2018 and January 2020, we invited 886 stroke survivors to participate in postal screening: 188/886 (21%) returned questionnaires and consented, of whom 76/188 (40%) were eligible and returned baseline forms; 64/76 (84%) returned six month follow-up questionnaires. Of the 39 allocated the intervention, 23 (59%) attended at least four sessions. At six months, there were no significant differences between the groups (adjusted mean differences in Fatigue Assessment Scale -0.619 (95% CI -4.9631, 3.694; p = 0.768), the Generalised Anxiety Disorder 7 -0.178 (95% CI -3.823, 3.467, p = 0.92), and the Patient Health Questionnaire -0.247 (95% CI -2.935, 2.442, p = 0.851). There were no between-group differences in quality of life, social participation or return to work. CONCLUSION: Patients can be recruited to a trial of this design. These data will inform the design of further trials in post-stroke fatigue.

Core Outcome Measures for Palliative and End-of-Life Research After Severe Stroke: Mixed-Method Delphi Study.

Background and Purpose: Stroke is the second commonest cause of death worldwide and a leading cause of severe disability, yet there are no published trials of palliative care in stroke. To design and evaluate palliative care interventions for people with stroke, researchers need to know what measurable outcomes matter most to patients and families, stroke professionals, and other service providers. Methods: A multidisciplinary steering group of professionals and laypeople managed the study. We synthesized recommendations from respected United Kingdom and international consensus documents to generate a list of outcome domains and then performed a rapid scoping literature review to identify potential outcome measures for use in future trials of palliative care after stroke. We then completed a 3-round, online Delphi survey of professionals, and service users to build consensus about outcome domains and outcome measures. Finally, we held a stakeholder workshop to review and finalize this consensus. Results: We generated a list of 36 different outcome domains from 4 key policy documents. The rapid scoping review identified 43 potential outcome measures that were used to create a shortlist of 16 measures. The 36 outcome domains and 16 measures were presented to a Delphi panel of diverse healthcare professionals and lay service users. Of 48 panelists invited to take part, 28 completed all 3 rounds. Shared decision-making and quality of life were selected as the most important outcome domains for future trials of palliative care in stroke. Additional comments highlighted the need for outcomes to be feasible, measurable, and relevant beyond the initial, acute phase of stroke. The stakeholder workshop endorsed these results. Conclusions: Future trials of palliative care after stroke should include pragmatic outcome measures, applicable to the evolving patient and family experiences after stroke and be inclusive of shared decision-making and quality of life.

Headache in transgender and gender-diverse patients: A narrative review.

OBJECTIVE: To summarize the unique aspects of managing headache in gender minorities and current research in this area including the potential relationship between gender-affirming hormone therapy (GAHT) and headache. BACKGROUND: The study of headache in gender minorities is intrinsically important. Gender minorities are medically underserved, and their medical care to date has been limited by socioeconomic disadvantages including stigma and an unsupportive clinical environment. Despite the rising population of transgender and gender-diverse adults and youth, headache research has also been limited. Knowledge of hormonal effects on headache in cisgender patients raises the question of possible effects of GAHT on transgender patients. METHODS/RESULTS: The manuscript is a narrative review of current best practices in treating transgender patients, including the use of appropriate terminology and ways to create a supportive environment. It also contains current guidelines on GAHT and reviews drug-drug interactions and secondary headache related to hormone therapy. We also review transgender headache research and related research on hormonal effects on headache in cisgender individuals. CONCLUSION: Creating a supportive environment for transgender and gender-diverse patients and being knowledgeable about GAHT are key to providing quality headache care. This review identifies further research needs for this population including the epidemiology of headache disorders in sexual minorities and the potential effects of GAHT on headache disorders in transgender patients.

Strangled by Dr Strangelove? Anarchic hand following a posterior cerebral artery territory ischemic stroke.

Anarchic hand is a rare condition where the complex movements of one hand appear to be goal directed and smoothly executed and yet are unintended and unwanted. Unlike alien hand syndrome, the patients recognise that the affected hand is part of their own body. They know the hand is theirs, but they deny having control over its actions. The syndrome has been reported after surgery on the corpus callosum and with brain tumours, aneurysms, degenerative diseases of the brain and uncommonly with stroke. We present a case of a 74-year-old man who developed an anarchic right hand following thrombolysis for a posterior cerebral artery territory ischemic stroke.

Gender Minority Stress, Psychiatric Comorbidities, and the Experience of Migraine in Transgender and Gender-Diverse Individuals: a Narrative Review.

PURPOSE OF REVIEW: This review aims to discuss the experience of migraine in transgender and gender-diverse individuals as it relates to other psychiatric comorbidities such as anxiety, depression, PTSD, and others. As this population faces stigma and discrimination, literature posits that gender minority stress can also contribute to the experience of pain in these individuals. RECENT FINDINGS: Though there is little explicit data on these topics, more recent studies have explored the concept of gender minority stress and how stigma and discrimination can affect health outcomes and overall perception of health. These findings, as well as data on psychiatric comorbidities in cisgender individuals with migraine, can be extrapolated to understand how gender minority individuals may experience migraine. Research has demonstrated that stigma and discrimination can affect health outcomes in the transgender and gender-diverse community. A recent study has shown that sexual minority stress associated with stigma, discrimination, and barriers to care can exacerbate migraine. It is known that psychiatric comorbidities such as anxiety, depression, and PTSD can affect migraine frequency and severity in cisgender individuals. Though there are no specific studies in the transgender and gender-diverse patient population, these highly prevalent mental health conditions could potentially contribute to their migraine experience. Hormones, as well, may affect mood in those on gender-affirming hormone therapy, with some studies exploring how this may have both a direct and indirect relationship with migraine. There are clear knowledge gaps that can be addressed by future research in these areas to better understand the migraine experience in transgender and gender-diverse individuals and improve overall care.

Practical guidance on use of TEARS-Q to diagnose post-stroke emotionalism.

OBJECTIVE: To evaluate, using a classification tree methodology, the ability of the Testing Emotionalism After Recent Stroke - Questionnaire (TEARS-Q) to determine the need for further assessment of post-stroke emotionalism and to identify those whose emotionalism is sufficiently clear that they need assessment for potential intervention. SETTING: Acute stroke units of nine Scottish hospitals in the context of a longitudinal cohort study of post-stroke emotionalism. SUBJECTS: A total of 228 stroke survivors recruited between October 1st 2015 and September 30th 2018, within two weeks of stroke. MEASURES: The measure was the self-report questionnaire TEARS-Q, constructed based on recognised diagnostic features of post-stroke tearful emotionalism. The reference standard was presence/absence of emotionalism on a diagnostic, semi-structured post-stroke emotionalism interview, administered at the same assessment point. RESULTS: Nine of 159 subjects scoring 0 or 1 on TEARS-Q were diagnosed with post-stroke emotionalism on the reference standard, compared to 11 of 21 subjects scoring 2 to 5 on TEARS-Q and 42 of 48 participants scoring 6 and above. Adding age, sex, deprivation, stroke type, stroke severity, mood, cognition, daily functioning and education did not improve the prediction accuracy sufficiently to change the classification tree. CONCLUSION: TEARS-Q reliably identifies those who need no further post-stroke emotionalism assessment, those who need further assessment to clarify diagnosis, and those who almost certainly have post-stroke emotionalism and may benefit from intervention.

Psychometric evaluation of a newly developed measure of emotionalism after stroke (TEARS-Q).

OBJECTIVE: To evaluate, psychometrically, a new measure of tearful emotionalism following stroke: Testing Emotionalism After Recent Stroke - Questionnaire (TEARS-Q). SETTING: Acute stroke units based in nine Scottish hospitals, in the context of a longitudinal cohort study of post-stroke emotionalism. SUBJECTS: A total of 224 clinically diagnosed stroke survivors recruited between October 1st 2015 and September 30th 2018, within 2 weeks of their stroke. MEASURES: The measure was the self-report questionnaire TEARS-Q, constructed based on post-stroke tearful emotionalism diagnostic criteria: (i) increased tearfulness, (ii) crying comes on suddenly, with no warning (iii) crying not under usual social control and (iv) crying episodes occur at least once weekly. The reference standard was presence/absence of emotionalism on a diagnostic, semi-structured post-stroke emotionalism interview, administered at the same assessment point. Stroke, mood, cognition and functional outcome measures were also completed by the subjects. RESULTS: A total of 97 subjects were female, with a mean age 65.1 years. 205 subjects had sustained ischaemic stroke. 61 subjects were classified as mild stroke. TEARS-Q was internally consistent (Cronbach's alpha 0.87). TEARS-Q scores readily discriminated the two groups, with a mean difference of -7.18, 95% CI (-8.07 to -6.29). A cut off score of 2 on TEARS-Q correctly identified 53 of the 61 stroke survivors with tearful emotionalism and 140 of the 156 stroke survivors without tearful emotionalism. One factor accounted for 57% of the item response variance, and all eight TEARS-Q items acceptably discriminated underlying emotionalism. CONCLUSION: TEARS-Q accurately diagnoses tearful emotionalism after stroke.

Experiences of augmented arm rehabilitation including supported self-management after stroke: a qualitative investigation.

OBJECTIVE: To explore the experiences of stroke survivors and their carers of augmented arm rehabilitation including supported self-management in terms of its acceptability, appropriateness and relevance. DESIGN: A qualitative design, nested within a larger, multi-centre randomized controlled feasibility trial that compared augmented arm rehabilitation starting at three or nine weeks after stroke, with usual care. Semi-structured interviews were conducted with participants in both augmented arm rehabilitation groups. Normalization Process Theory was used to inform the topic guide and map the findings. Framework analysis was applied. SETTING: Interviews were conducted in stroke survivors' homes, at Glasgow Caledonian University and in hospital. PARTICIPANTS: 17 stroke survivors and five carers were interviewed after completion of augmented arm rehabilitation. INTERVENTION: Evidence-based augmented arm rehabilitation (27 additional hours over six weeks), including therapist-led sessions and supported self-management. RESULTS: Three main themes were identified: (1) acceptability of the intervention (2) supported self-management and (3) coping with the intervention. All stroke survivors coped well with the intensity of the augmented arm rehabilitation programme. The majority of stroke survivors engaged in supported self-management and implemented activities into their daily routine. However, the findings suggest that some stroke survivors (male >70 years) had difficulties with self-management, needing a higher level of support. CONCLUSION: Augmented arm rehabilitation commencing within nine weeks post stroke was reported to be well tolerated. The findings suggested that supported self-management seemed acceptable and appropriate to those who saw the relevance of the rehabilitation activities for their daily lives, and embedded them into their daily routines.

Non-invasive brain stimulation in Stroke patients (NIBS): A prospective randomized open blinded end-point (PROBE) feasibility trial using transcranial direct current stimulation (tDCS) in post-stroke hemispatial neglect.

Up to 80% of people who experience a right-hemisphere stroke suffer from hemispatial neglect. This syndrome is debilitating and impedes rehabilitation. We carried out a clinical feasibility trial of transcranial direct current stimulation (tDCS) and a behavioural rehabilitation programme, alone or in combination, in patients with neglect. Patients >4 weeks post right hemisphere stroke were randomized to 10 sessions of tDCS, 10 sessions of a behavioural intervention, combined intervention, or a control task. Primary outcomes were recruitment and retention rates, with secondary outcomes effect sizes on measures of neglect and quality of life, assessed directly after the interventions, and at 6 months follow up. Of 288 confirmed stroke cases referred (representing 7% of confirmed strokes), we randomized 8% (0.6% of stroke cases overall). The largest number of exclusions (91/288 (34%)) were due to medical comorbidities that prevented patients from undergoing 10 intervention sessions. We recruited 24 patients over 29 months, with 87% completing immediate post-intervention and 67% 6 month evaluations. We established poor feasibility of a clinical trial requiring repeated hospital-based tDCS within a UK hospital healthcare setting, either with or without behavioural training, over a sustained time period. Future trials should consider intensity, duration and location of tDCS neglect interventions.Trial registration: ClinicalTrials.gov identifier: NCT02401724.

Exercise and Migraine Prevention: a Review of the Literature.

PURPOSE OF REVIEW: This review intends to characterize the recent literature pertaining to the role of aerobic exercise in the prevention of migraine. Areas of consensus within that literature may be used to guide clinical practice, allowing for the promulgation of evidence-based practice recommendations. RECENT FINDINGS: The past decade has seen the publication of numerous high-quality studies that explore aspects of exercise's effects on migraine prevention, including its success as a stand-alone prevention strategy, as well as its non-inferiority to some pharmacologic preventive measures. Exercise often tops providers' lists of recommended lifestyle modifications that help reduce migraine burden. Biologically, exercise suppresses inflammatory modulators, including numerous cytokines, and stress hormones, like growth hormone and cortisol. Exercise has also been shown to affect microvascular health, which may be implicated in cortical spreading depression. Psychologically, there is evidence that exercise improves migraine self-efficacy and internalizes the locus of control, leading to reduced migraine burden. Randomized control trials have demonstrated that a sufficiently rigorous aerobic exercise regimen alone is sufficient to yield a statistically significant reduction in migraine frequency, intensity, and duration. Higher-intensity training appears to confer more benefit. Studies have also demonstrated non-inferiority of exercise compared with certain pharmacologic prophylactic interventions, like topiramate. However, the addition of exercise to a traditional preventive regimen may provide added benefit. Special populations, like those with comorbid neck pain or tension headache, may benefit from exercise; and patients who cannot tolerate high-impact exercise may even benefit from low-impact exercise like yoga. Therefore, exercise is a reasonable evidence-based recommendation for migraine prevention.

Home-Time Is a Feasible and Valid Stroke Outcome Measure in National Datasets.

Background and Purpose- Home-time (HT) is a stroke outcome measure based on time spent at home after stroke. We hypothesized that HT assessment would be feasible and valid using national data. Methods- We linked the Scottish Stroke Care Audit to routine healthcare data and calculated 90-day HT for all strokes, 2005 to 2017. We described prognostic validity (Spearman rank correlation) of HT to baseline factors. Results- We were able to calculate HT for 101 969 strokes (99.3% of total Scottish strokes). Mean HT was 46 days (95% CI, 45.8-46.2; range, 0-90). HT showed consistent correlation with our prespecified prognostic factors: age: ρ, -0.35 (95% CI, -0.35 to -0.36); National Institutes of Health Stroke Scale score, -0.54 (95% CI, -0.52 to -0.55); and 6 simple variables (ordinal), -0.61 (95% CI, -0.61 to -0.62). Conclusions- HT can be derived at scale using routine clinical data and appears to be a valid proxy measure of functional recovery. Other national databases could use HT as a time and cost efficient measure of medium and longer-term outcomes.

Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study.

BACKGROUND: Case fatality after total anterior circulation stroke is high. Our objective was to describe the experiences and needs of patients and caregivers, and to explore whether, and how, palliative care should be integrated into stroke care. METHODS: From 3 stroke services in Scotland, we recruited a purposive sample of people with total anterior circulation stroke, and conducted serial, qualitative interviews with them and their informal and professional caregivers at 6 weeks, 6 months and 1 year. Interviews were transcribed for thematic and narrative analysis. The Palliative Care Outcome Scale, EuroQol-5D-5L and Caregiver Strain Index questionnaires were completed after interviews. We also conducted a data linkage study of all patients with anterior circulation stroke admitted to the 3 services over 6 months, which included case fatality, place of death and readmissions. RESULTS: Data linkage (n = 219) showed that 57% of patients with total anterior circulation stroke died within 6 months. The questionnaires recorded that the patients experienced immediate and persistent emotional distress and poor quality of life. We conducted 99 interviews with 34 patients and their informal and professional careers. We identified several major themes. Patients and caregivers faced death or a life not worth living. Those who survived felt grief for a former life. Professionals focused on physical rehabilitation rather than preparation for death or limited recovery. Future planning was challenging. "Palliative care" had connotations of treatment withdrawal and imminent death. INTERPRETATION: Major stroke brings likelihood of death but little preparation. Realistic planning with patients and informal caregivers should be offered, raising the possibility of death or survival with disability. Practising the principles of palliative care is needed, but the term "palliative care" should be avoided or reframed.

Assessment of enamel discoloration in vitro following exposure to cigarette smoke and emissions from novel vapor and tobacco heating products.

PURPOSE: To evaluate in vitro enamel sample discoloration following exposure to a scientific reference cigarette (3R4F) or emissions from next generation tobacco and nicotine products (NGPs) such as electronic cigarettes (EC) and tobacco heating products (THP). METHODS: Bovine enamel blocks (6.5 × 6.5 mm) were prepared and pre-incubated with human or artificial saliva, to form a pellicle layer before exposure to either particulate matter (PM) or whole aerosols. PM was prepared by capturing 3R4F cigarette smoke (CS), a commercial THP (THP1.0) or a novel vapor product (NVP)/next generation e-cigarette aerosols on Cambridge filter pads followed by elution with dimethyl sulfoxide (DMSO). Ten enamel samples were exposed to each PM for 14 days. For aerosol exposure, 12 enamel samples were exposed (200 puffs per day, for 5 consecutive days) to 3R4F CS or THP1.0 and NVP aerosols. Control samples were incubated with DMSO (PM study) or phosphate buffered saline (PBS, aerosol study). Individual enamel sample color readings (L*, a*, b*) were measured at baseline and on each exposure day. Mean ΔL*, Δa*, Δb* and ΔE values were calculated for each product or control. A one-way ANOVA was used to assess the differences between the products and controls. The Tukey procedure for pairwise comparisons was also used. RESULTS: At all timepoints, 3R4F PM and CS induced enamel discoloration that was statistically significant (< 0.0001) when compared to THP1.0 or NVP. After 14-day PM exposure, mean ΔE values were 29.4± 3.6, 10.5 ± 2.3, 10.7 ± 2.6 and 12.6 ± 2.0 for 3R4F, THP1.0, NVP and DMSO control respectively. After 5-day CS or aerosol exposure, mean ΔE values were 26.2 ± 3.2, 3.6 ± 1.9, 3.4 ± 1.3, 5.3 ± 0.8 for 3R4F CS, THP1.0, NVP or PBS control, respectively. Both exposure methods demonstrated that THP1.0 and NVP induced minimal staining, mean ΔL* , Δa* , Δb* and ΔE values were comparable to DMSO or PBS controls. CLINICAL SIGNIFICANCE: For the first time, diverse NGPs across the risk continuum were assessed in vitro for their impact on enamel staining. CS exposure significantly increased the level of bovine enamel sample discoloration, whereas THP1.0 or NVP exposure resulted in values comparable to the controls.

Norbin Stimulates the Catalytic Activity and Plasma Membrane Localization of the Guanine-Nucleotide Exchange Factor P-Rex1.

P-Rex1 is a guanine-nucleotide exchange factor (GEF) that activates the small G protein (GTPase) Rac1 to control Rac1-dependent cytoskeletal dynamics, and thus cell morphology. Three mechanisms of P-Rex1 regulation are currently known: (i) binding of the phosphoinositide second messenger PIP3, (ii) binding of the Gßγ subunits of heterotrimeric G proteins, and (iii) phosphorylation of various serine residues. Using recombinant P-Rex1 protein to search for new binding partners, we isolated the G-protein-coupled receptor (GPCR)-adaptor protein Norbin (Neurochondrin, NCDN) from mouse brain fractions. Coimmunoprecipitation confirmed the interaction between overexpressed P-Rex1 and Norbin in COS-7 cells, as well as between endogenous P-Rex1 and Norbin in HEK-293 cells. Binding assays with purified recombinant proteins showed that their interaction is direct, and mutational analysis revealed that the pleckstrin homology domain of P-Rex1 is required. Rac-GEF activity assays with purified recombinant proteins showed that direct interaction with Norbin increases the basal, PIP3- and Gßγ-stimulated Rac-GEF activity of P-Rex1. Pak-CRIB pulldown assays demonstrated that Norbin promotes the P-Rex1-mediated activation of endogenous Rac1 upon stimulation of HEK-293 cells with lysophosphatidic acid. Finally, immunofluorescence microscopy and subcellular fractionation showed that coexpression of P-Rex1 and Norbin induces a robust translocation of both proteins from the cytosol to the plasma membrane, as well as promoting cell spreading, lamellipodia formation, and membrane ruffling, cell morphologies generated by active Rac1. In summary, we have identified a novel mechanism of P-Rex1 regulation through the GPCR-adaptor protein Norbin, a direct P-Rex1 interacting protein that promotes the Rac-GEF activity and membrane localization of P-Rex1.

Stroke patients admitted within normal working hours are more likely to achieve process standards and to have better outcomes.

BACKGROUND: The presence of a 'weekend' effect has been shown across a range of medical conditions, but has not been consistently observed for patients with stroke. AIMS: We investigated the impact of admission time on a range of process and outcome measures after stroke. METHODS: Using routine data from National Scottish data sets (2005-2013), time of admission was categorised into weekday, weeknight and weekend/public holidays. The main process measures were swallow screen on day of admission (day 0), brain scan (day 0 or 1), aspirin (day 0 or 1), admission to stroke unit (day 0 or 1), and thrombolysis administration. After case-mix adjustment, multivariable logistic regression was used to estimate the OR for mortality and discharge to home/usual place of residence. RESULTS: There were 52,276 index stroke events. Compared to weekday, the adjusted OR (95%CI) for early stroke unit admission was 0.81 (0.77 to 0.85) for weeknight admissions and 0.64 (0.61 to 0.67) for weekend/holiday admissions; early brain scan 1.30 (0.87 to 1.94) and 1.43 (0.95 to 2.18); same day swallow screen 0.86 (0.81 to 0.91) and 0.85 (0.81 to 0.90); thrombolysis 0.85 (0.75 to 0.97) and 0.85 (0.75 to 0.97), respectively. Seven-day mortality, 30-day mortality and 30-day discharge for weekend admission compared to weekday was 1.17 (1.05 to 1.30); 1.08 (1.00 to 1.17); and 0.90 (0.85 to 0.95), respectively. CONCLUSIONS: Patients with stroke admitted out of hours and at weekends or public holidays are less likely to be managed according to current guidelines. They experience poorer short-term outcomes than those admitted during normal working hours, after correcting for known independent predictors of outcome and early mortality.